US11873316B2ActiveUtilityPatentIndex 83
Compositions and methods for phosphoramidite and oligonucleotide synthesis
Est. expiryNov 23, 2036(~10.4 yrs left)· nominal 20-yr term from priority
Inventors:BUTLER DAVID CHARLES DONNELLKANDASAMY PACHAMUTHUMARAPPAN SUBRAMANIANPAIK IK-HYEONKUMARASAMY JAYAKANTHANBOMMINENI GOPAL REDDY
C07H 1/06C07H 19/10C07H 19/207C07H 21/00C07F 9/65844C07H 1/00C07H 19/16
83
PatentIndex Score
10
Cited by
265
References
18
Claims
Abstract
The present disclosure, among other things, provides technologies for oligonucleotide synthesis. In some embodiments, the present disclosure provides phosphoramidites and methods for synthesis thereof. In some embodiments, provided methods provides higher yields and/or purities. In some embodiments, provided methods remove byproducts without contact with an aqueous solution.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A method for preparing a phosphoramidite, comprising steps of:
a) providing a preparation comprising a phosphoramidite product and one or more reaction byproducts of the synthesis of the phosphoramidite; and
b) performing a filtration step on the preparation to provide a filtrate, wherein the filtrate contains a reduced level of the one or more reaction byproducts relative to the product as compared to that level present in the preparation prior to the filtration step,
wherein:
after the phosphoramidite product is formed, no solution comprising the phosphoramidite product is contacted with water of more than 100 mole equivalents of the phosphoramidite; and
the phosphoramidite has the structure of formula I:
wherein:
BA is
wherein R is hydrogen or optionally substituted C 1-6 aliphatic;
SU is
R 5 s is R′ or —OR′;
wherein:
(1) R 2s is —F or —OCH 2 CH 2 OMe, and
or
(2) R 2s is —F, —H, or —OCH 2 CH 2 OMe, and
each R′ is independently —R, —C(O)R, —CO 2 R, or —SO 2 R, or:
two or more R′ are taken together with their intervening atoms to form an optionally substituted monocyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aryl 3-30 membered ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; and
each R is independently hydrogen, or an optionally substituted group selected from C 1-30 aliphatic, C 1-30 heteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, C 6-30 aryl, a 5-30 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3-30 membered heterocyclic ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.
2. The method of claim 1 , wherein the preparation comprises a solution and one or more solids.
3. The method of claim 2 , wherein the solution comprises the phosphoramidite product.
4. The method of claim 3 , wherein the one or more solids comprise one or more reaction byproducts.
5. The method of claim 4 , wherein R 5S is DMTrO-.
6. The method of claim 5 , wherein R 2s is —H.
7. The method of claim 4 , comprising purifying the phosphoramidite product using silica gel column chromatography, wherein the silica gel is treated with an anhydrous acetonitrile.
8. The method of claim 5 , wherein R 2s is —F.
9. The method of claim 8 , wherein
10. The method of claim 8 , wherein
11. The method of claim 5 , wherein R 2s is —OCH 2 CH 2 OMe.
12. The method of claim 11 , wherein
13. The method of claim 11 , wherein BA is
14. The method of claim 4 , wherein BA is
in which R is C 1-6 alkyl.
15. The method of claim 4 , wherein BA is
in which R is isopropyl.
16. The method of claim 1 , wherein the prepared phosphoramidite has a purity of 90% or more.
17. The method of claim 1 , wherein the prepared phosphoramidite has a purity of 95% or more.
18. The method of claim 1 , wherein the prepared phosphoramidite has a purity of 96% or more.Cited by (0)
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